CN105732683A - Dipeptide boric acid composed of carboxylic acid and alpha-amino acid as well as ester compound thereof, and preparation method and application of dipeptide boric acid and ester compound thereof - Google Patents

Dipeptide boric acid composed of carboxylic acid and alpha-amino acid as well as ester compound thereof, and preparation method and application of dipeptide boric acid and ester compound thereof Download PDF

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CN105732683A
CN105732683A CN201610186292.1A CN201610186292A CN105732683A CN 105732683 A CN105732683 A CN 105732683A CN 201610186292 A CN201610186292 A CN 201610186292A CN 105732683 A CN105732683 A CN 105732683A
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compound
alkyl
boric acid
alkoxyl
cancer
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CN105732683B (en
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雷萌
朱永强
冯华云
王成
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Nanling Chuangte Pharmaceutical Technology Co ltd
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Nanjing Forestry University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Abstract

The invention belongs to the field of drug synthesis and in particular relates to a series of novel peptide boric acids as well as an ester compound or pharmaceutical salt thereof, and a preparation method and application of the peptide boric acids as well as the ester compound or pharmaceutical salt thereof in pharmacodynamics. A structure of the peptide boric acid and the ester compound or pharmaceutical salt thereof is shown in a formula I (described in the specification). The compound provided by the invention can be used for preparing a proteasome inhibitor and can further be used for treating solid tumours and blood tumours, wherein the solid tumours are selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, nasopharynx cancer and leukemia; and the blood tumours are selected from multiple myeloma, mantle cell lymphoma and histiocytic lymphoma.

Description

The dipeptide boronic acid of one class carboxylic acid and alpha amino acid composition and ester type compound, preparation method and its usage
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to the preparation method of series of new peptide boric acid and ester type compound thereof and the application on pharmacodynamics thereof.
Background technology
At present, cancer is one of harm topmost disease of human health.Although the treatment of current cancer has been achieved for very big progress in fields such as operative treatment, chemotherapy, radiotherapies, but can't fundamentally treat cancer.Although the cancer therapy drug of listing has certain curative effect at present, but they have serious toxic and side effects.Therefore, how further investigated and research go out to send, from effective tumor targets, the new type anticancer medicine studying targeting becomes the task of top priority of medical personal.
Ubiquitin-Proteasome Pathway (Ubiquitin-ProteasomePathway, it is called for short UPP) it is the main path of intracellular protein system degraded, and participate in cellular processes important on much physiology, including signal transduction, immunne response, Non-adhesion inhibition index and cell cycle progress.The morbidity etc. of this approach and cardiovascular and cerebrovascular disease, cancer and nervous system degenerative disease suffers from important relation.Use some effective inhibitor to suppress protein that in this approach, excessive degradation is important will provide new thinking for the treatment of above-mentioned disease.For this novel target spot, within 2003, first proteasome inhibitor bortezomib (PS-341) obtains FDA approval listing, is used for treating recurrent myeloma.This medicine in 2004 goes through again to list in European Union, again for multiple myeloma.In JIUYUE, 2005, this medicine is introduced by Xi'an Yang Sen, first in China's Guangzhou listing.2005, this medicine obtained " PrixGalien " prize of the Nobel Prize title with the world of medicine simultaneously in France, Holland and Belgium.It is approved by the fda in the united states for again treatment relapsed or stubborn lymphoma mantle cell (MantleCellLymphoma is called for short MCL) on July 11st, 2007, becomes the currently the only FDA of the obtaining approval medicine for treating MCL.FDA ratifies Bortezomib can carry out subcutaneous administration, and this not only makes being absorbed as easily of Bortezomib, is also greatly improved patient's toleration to Bortezomib, decreases side effect.
The sales volume of Bortezomib in 2014 reaches 30.69 hundred million dollars becomes one of global best-selling tumour medicine top20.Bortezomib is every 3.5 milligrams about 10,000 three thousand yuan in Chinese market price, treats a period expense about 40,000 yuan, and so expensive expense is very heavy financial burden for many patients.And, current clinical data shows, this kind of medicine there is also the side effect that comparison is many, as weak, nauseating in fatigue, diarrhoea and neuropathy etc..Therefore, how developing a kind of high therapeutic protein enzyme body inhibitor medicaments cheap, that toxic and side effects is low is that we are presently required key problems-solving.
For the target spot that this curative effect is confirmed, we devise the boric acid albuminoid enzyme body inhibitor that a series of structure is brand-new.
Summary of the invention
It is an object of the invention to synthesize a series of novel structure and there is novel boric acid and the ester type compound thereof of proteasome inhibition function.As 20S proteasome inhibitor, they can effectively block tumor cell proliferation, induced tumor apoptosis, thus being used for prevention and the treatment of humans and animals multiple disease such as malignant tumor.
The preparation method that it is a further object of the present invention to provide a kind of above-mentioned peptide boric acid and ester type compound thereof.
It is a still further object of the present invention to provide a kind of above-mentioned peptide boric acid and ester type compound application in preparing antitumor drug thereof.
The purpose of the present invention specifically can be reached by following measures:
A kind of peptide boric acid and ester type compound thereof, its structure shown in formula I,
Wherein:
R1Selected from C1～10Alkyl, C1～10Alkoxyl, C1～10Alcoxyl C1～10Alkyl, phenyl, naphthyl, tetralyl or heterocyclic radical, or optionally by C1～4Alkyl, C1～4Alkoxyl, C1～4Cycloalkyl, halogen or halo C1～4Alkyl replaces；R1It is preferably C1～10Alkyl, C1～10Alkoxyl, C1～10Alkoxyl-methyl, C1～10Alkoxyl oxygen alkyl ethyl, phenyl, pyrazinyl, pyridine radicals, naphthyl, tetralyl, or optionally by C1～4Alkyl, C1～4Alkoxyl, halogen or halo C1～4Alkyl replaces.
Further, R1More preferably:
Wherein R3And R4Independently selected from hydrogen, methyl, methoxyl group, ethyl, ethyoxyl, chlorine, bromine, fluorine or trifluoromethyl.
R2Selected from C1～10Alkyl, C3～6Cycloalkyl or Heterocyclylalkyl, phenyl, naphthyl or indyl, or optionally by C1～4Alkyl, C1～4Alkoxyl, cyano group, nitro, hydroxyl, sulfydryl, amino or halogen substiuted；R2It is preferably phenyl, methoxyl group, first sulfydryl, cyclohexyl, or optionally by C1～4Alkyl, C1～4Alkoxyl, nitro or halogen substiuted.
Z1Or Z2Independently selected from hydroxyl, C1～10Alkyl, C1～10Alkoxyl or aryloxy group, or B, Z1And Z2Collectively form the heterocyclic group containing N, S or O or B and Z1And Z2Collectively form the group containing O heterocycle, and what be connected with boron atom is oxygen atom.Preferably, Z1Or Z2Independently selected from hydroxyl, C1～10Alkyl, C1～10Alkoxyl or aryloxy group, or B, Z1And Z2Collectively form boric acid-australene alkane diol ester or B and Z1And Z2Collectively form borate, and what be connected with boron atom is oxygen atom.It is further preferred that Z1Or Z2It is independently selected from hydroxyl or B, Z1And Z2Collectively form boric acid-australene alkane diol ester or B, Z1And Z2Collectively form diethanolamine ester and other prodrugs.
R of the present invention1、R2In group " optionally by ... replace " refer to R1、R2Group can be replaced by these groups, it is also possible to do not replaced by these groups, be namely not limited in situation about being replaced by cited these groups, also include situation about not replaced by these cited groups.This expression way and " R1For substituted or non-substituted C1～10Alkyl, C3～6Cycloalkyl or Heterocyclylalkyl, phenyl, naphthyl or indyl, wherein substituent group is C1～4Alkyl, C1～4Alkoxyl, cyano group, hydroxyl, sulfydryl, amino or halogen " expression way identical, but substituted or non-substituted restriction not only narrowly refers to C1～10Alkyl, but expand all described groups to, namely include substituted or non-substituted C3～6Cycloalkyl or Heterocyclylalkyl, substituted or non-substituted benzyl, substituted or non-substituted menaphthyl, substituted or non-substituted indole methyl etc., wherein substituent group is C1～4Alkyl, C1～4Alkoxyl, cyano group, hydroxyl, sulfydryl, amino or halogen.
Term " alkyl " is used for representing saturated hydrocarbyl, C1～10Alkyl refer to the saturated hydrocarbyl containing 1～10 carbon atom, C1～4Alkyl refer to the saturated hydrocarbyl containing 1～4 carbon atom.
Term " cycloalkyl " refers to non-aromatic carbocyclyl, including the alkyl of cyclisation.Cycloalkyl can include bicyclo-or multi-loop system.The example of cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, C3～6Cycloalkyl refer to the cycloalkyl containing 3～6 carbon atoms.
Term " benzyl " refers to benzyl, and the benzyl of replacement refers to that at least one hydrogen atom is replaced by non-hydrogen partial on the phenyl ring of benzyl, and the substituent group of benzyl can be halogen ,-CN ,-OH ,-SH ,-NH2, the straight or branched alkyl of 1-6 carbon, the straight or branched alkyl of the replacement of 1-6 carbon.
Term " Heterocyclylalkyl " refers to non-aromatic assorted carbocylic radical, and including the alkyl of cyclisation, wherein one or more ring carbons are replaced by hetero atom such as O, N or S atom.Heterocyclylalkyl preferably has 3,4,5,6 or 7 ring member nitrogen atoms.
Term " heterocyclic radical " refers to the cyclic group containing hetero atom O, N or S, such as furan, thiophene, pyrroles, thiazole, imidazoles, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinolin, indole, benzofuran, purine, acridine etc..
" 1-menaphthyl " refers to
" 2-menaphthyl " refers to
" indole methyl " refers to
" alkoxyl " refers to-O-alkyl group, and its carbon number is generally 1～10.The example of alkoxyl includes methoxyl group, ethyoxyl, propoxyl group (e.g., n-propoxyl group and isopropoxy), t-butoxy etc..
" aryl " refers to aromatic carbocyclyl groups, including monocycle or polycyclic aromatic hydrocarbon such as phenyl, naphthyl, anthryl, phenanthryl etc..
" aryloxy group " refers to-O-aryl, and the concept of aryl is as it has been described above, the most preferred example of aryloxy group is phenoxy group.
" halogen " includes fluorine, chlorine, bromine and iodine.
R in the compounds of this invention2Group can be raceme, it is possible to have optical activity, the R in the present invention2Group is preferably R configuration.
The compounds of this invention can in order to prepare antitumor drug, and its total syntheti c route is:
Each group R in this reaction equation1, R2, Z1And Z2Defined as described above, route one is phthalimide and ethyl chloroacetate production (II-1), formula (II-1) and alanine react production (II-2), formula (II-2) and 8-quinolin-2-ylamine production (II-3), formula (II-3) and aryl iodide react production (II-4), formula (II-4) reacts production (II-5) when boron trifluoride diethyl etherate, and formula (II-5) reacts production (II) when ethylenediamine；Route two is that formula (III-1) is at SOCl2Effect is descended and methanol is obtained by reacting formula (III).The formula (II) of route one and route two, formula (III)) compound under peptide condensing agent respectively with R1Production (I-1) compound, formula (I-1) compound saponification acidifying production again (I-2) compound, formula (I-2) compound under peptide condensing agent with the semicarbazide hydrochloride of borate or trifluoroacetate condensation production (I-3) compound, formula (I-3) compound production in acid condition (IV) compound, last formula (IV) compound generates formula V compound when hot ethyl acetate.
The preparation method of the compounds of this invention described below:
R1, R2, Z1And Z2As defined above.
The preparation method of Compound II per comprises the following steps that
1) phthalimide and ethyl chloroacetate are obtained by reacting the compound of formula (II-1) structure under triethylamine effect；
2) compound of formula (II-1) structure and alanine are at Na2CO3And H2The compound of production (II-2) structure when O；
3) compound of formula (II-2) structure is first at SOCl2Effect under generate acyl chlorides, then with the compound of 8-quinolin-2-ylamine production in the basic conditions (II-3)；
4) compound of formula (II-3) structure and aryl iodide compound of production (II-4) when palladium and silver tetrafluoroborate；
5) compound of formula (II-4) structure when boron trifluoride diethyl etherate with the compound of methanol production (II-5)；
6) compound of formula (II-5) structure when ethylenediamine with the compound of methanol production (II).
The preparation method of compound (III) comprises the following steps that
The aminoacid of formula (III-1) structure is at SOCl2The lower compound being obtained by reacting formula (III) structure with methanol of effect.
The preparation method of compound (I) comprises the following steps that
1) formula (II) and formula (III)) shown in compound under peptide condensing agent with R1Production (I-1) compound；
2) compound of formula (I-1) structure occurs saponification to generate its sodium salt in the basic conditions, then generates compound (I-2) in acid condition；
3) formula (I-2) compound under peptide condensing agent with the semicarbazide hydrochloride of borate or trifluoroacetate condensation production (I-3) compound；
4) formula (I-3) compound production (IV) compound when isobutaneboronic acid.
5) formula (IV) compound generates formula V compound when boiling ethyl acetate
Peptide condensing agent common in above-mentioned reaction is N, N-dicyclohexyl-carbodiimide (is abbreviated as DCC), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (being abbreviated as EDC HCl), 1-hydroxy benzo triazole (is abbreviated as HOBt) or isobutyl chlorocarbonate.
The present inventor experiments prove that, compound in the present invention has activity and the anti-tumor activity of good protease inhibition body, part of compounds shows good proteasome inhibition activity and antitumor action under nanomolar range, has the using value preparing proteasome inhibitor or antitumor drug aspect.Meanwhile, the compounds process for production thereof productivity designed by the present invention is higher, and technique is simple, is suitably adapted for industrialized production.
Detailed description of the invention
The synthesis of Part I compound
The preparation of the compound of the present invention can be implemented as follows:
One, the preparation of compound (II)
1, the preparation of N-ethyl acetate phthalimide II-1:
Phthalimide is dissolved in DMF, adds triethylamine, 0 DEG C of downhill reaction system drips ethyl chloroacetate, react 2 hours after being slowly increased to room temperature, reactant liquor is poured in frozen water, filter, filter cake frozen water washs, and vacuum drying obtains pure (Formula II-1) compound.
2, the preparation of the alanine II-2 of N-phthalyl Asia protection:
Compound II per-1 and ALANINE are dissolved in H2In O, add Na2CO3Reacting 2 hours, add 1NHCl and regulate pH value to 2, filter, namely vacuum drying obtains pure (Formula II-2) compound.
3, the preparation of Compound II per-3:
Compound II per-2 is dissolved in CH2Cl2In, add SOCl2Condensing reflux 6 hours, removes solvent under reduced pressure.8-quinolin-2-ylamine is dissolved in CH with DIPEA2Cl2In, at-20 DEG C, drip CH2Cl2The acyl chlorides dissolved, is slowly increased to room temperature reaction overnight.Remove solvent under reduced pressure, obtain Compound II per-3 through column chromatography for separation.
3, the preparation of Compound II per-4:
Compound II per-3 is dissolved in the tert-butyl alcohol, adds palladium, silver tetrafluoroborate and alkyl iodide, condensing reflux 24 hours, after returning to room temperature, use CH2Cl2Dilution, adds triethylamine and reacts 3 hours, cross kieselguhr, remove solvent under reduced pressure, obtain Compound II per-4 through column chromatography for separation.
4, the preparation of Compound II per-5:
Being dissolved in MeOH by Compound II per-4 in heavy wall pressure bottle, drip boron trifluoride ether solution, 100 DEG C of reactions overnight, add triethylamine stirring, remove solvent under reduced pressure, be dissolved in CH2Cl2After, respectively with pickling (10% hydrochloric acid), alkali cleaning (5% sodium bicarbonate) and saturated common salt are washed, desiccant dryness (anhydrous sodium sulfate and anhydrous magnesium sulfate).Filter desiccant, evaporated under reduced pressure solvent, obtain Compound II per-5 through column chromatography for separation.
4, the preparation of Compound II per:
Being dissolved in MeOH by Compound II per-5, add ethylenediamine, 70 DEG C of condensing refluxes react 5 hours, filter, filtrate decompression solvent evaporated, obtain Compound II per through column chromatography for separation.
Three, the preparation of compound (III)
By compound (III-1 is dissolved in MeOH, drips SOCl2, rise to ambient temperature overnight, evaporated under reduced pressure solvent, obtain Compound II per I after dropwising under cryosel bath).
Three, the preparation of compound (I)
1, the preparation of compound I-1:
By R1-COOH is dissolved in CH2Cl2In, add 1-hydroxy benzo triazole (HOBt), after reacting 10 minutes at-5 DEG C, add peptide condensing agent (EDC HCl), react 20 minutes, add compound I or III, after 10 minutes, add N, N-diisopropylethylamine (DIPEA), stirs overnight under room temperature after reacting half an hour.Reactant liquor is respectively with pickling (10% hydrochloric acid), alkali cleaning (5% sodium bicarbonate) and saturated common salt washing, desiccant dryness (anhydrous sodium sulfate and anhydrous magnesium sulfate).Filter desiccant, evaporated under reduced pressure solvent, obtain compound I-1 through column chromatography for separation.
2, the preparation of compound I-2:
Compound I-1 is dissolved in MeOH, adds LiOH H2O and H2O, after reacting 3 hours, removes MeOH under reduced pressure, adds 1NHCl and regulates pH value to 2, is extracted with ethyl acetate separatory, and namely evaporated under reduced pressure solvent obtains compound I-2.
3, the preparation of compound I-3:
Compound I-2 is dissolved in CH2Cl2In, add 1-hydroxy benzo triazole (HOBt), after reacting 10 minutes at-5 DEG C, add peptide condensing agent (EDC HCl), react 20 minutes, add hydrochlorate or the trifluoroacetate of borate, after 10 minutes, add N, N-diisopropylethylamine (DIPEA), stirs overnight under room temperature after reacting half an hour.Reactant liquor is respectively with pickling (10% hydrochloric acid), alkali cleaning (5% sodium bicarbonate) and saturated common salt washing, desiccant dryness (anhydrous sodium sulfate and anhydrous magnesium sulfate).Filter desiccant, evaporated under reduced pressure solvent, obtain compound I-3 through column chromatography for separation.
4, the preparation of compound IV
Being dissolved in MeOH by compound I-3, add isobutaneboronic acid, normal hexane and 1NHCl, reaction is overnight.Separatory, with extracting normal hexane in MeOH 2 times mutually, then washs methanol phase 1 time with normal hexane, removes methanol under reduced pressure, use CH2Cl2Aqueous phase extracted 2 times, by saturated common salt water washing organic facies to aqueous phase in neutrality.Evaporated under reduced pressure solvent, obtains compound IV through column chromatography for separation.
5, the preparation of compound V
By the amine containing glycol or acid-soluble in ethyl acetate at 74 DEG C, add compound IV, be cooled to 60 DEG C, react 3 hours, then be cooled to 25 DEG C and react overnight.Filtering, vacuum drying obtains pure (Formula V) compound.
The preparation of compounds of the present invention is described with the synthesis of particular compound below:
One, the preparation of compound in formula (II):
1, the preparation of N-ethyl acetate phthalimide (Compound II per-1)
By phthalimide (7.36g, 50mmol) it is dissolved in DMF (25mL), add triethylamine (9mL, 65mmol), 0 DEG C of downhill reaction system drips ethyl chloroacetate (5.7mL, 60mmol), after being slowly increased to room temperature, TLC detects reaction, and 2h reaction terminates, reactant liquor is poured in frozen water, filtering, filter cake frozen water washs, and vacuum drying obtains pure N-ethyl acetate phthalimide 8.67g, yield 79.1%, mp81.4-83.6 DEG C.1HNMR (400MHz, CDCl3)δ1.44(-CH3, t, J=7.1Hz, 3H), 4.48 (-CH2, q, J=7.1Hz, 2H), 7.80-7.85 (-Ph, m, 2H), 7.93-7.99 (-Ph, m, 2H).MS (ESI): m/z220.1 [M+H]+。
2, the preparation of the alanine (Compound II per-2) of N-phthalyl Asia protection:
Compound II per-1 (21.9g, 100mmol) and ALANINE (8.9g, 100mmol) are dissolved in H2In O (100mL), add Na2CO3(10.6g, 100mmol), TLC detects reaction, and 2h reaction terminates, and adds 1NHCl and regulates pH value to 2, filters, and namely vacuum drying obtains pure (Formula II-2) compound 17.4g, yield 79.3%, mp145.8-146.6 DEG C.1HNMR (400MHz, CDCl3)δ1.71(-CH3, d, J=7.4Hz, 3H), 5.02 (-CH, q, J=7.4Hz, 1H), 7.69-7.75 (-Ph, m, 2H), 7.82-7.88 (-Ph, m, 2H).MS (ESI): m/z218.2 [M-H]-。
3, the preparation of (S)-2-(phthalimide-based)-N-(8 quinolyl) propionic acid amide. (Compound II per-3):
Compound II per-2 (17.37g, 79.25mmol) is dissolved in CH2Cl2(80mL), in, SOCl is added2(29mL, 396.25mmol) condensing reflux 6 hours, removes solvent under reduced pressure.8-quinolin-2-ylamine (11.4g, 79.25mmol) is dissolved in CH with DIPEA (20.5g, 158.5mmol)2Cl2(103mL), in, at-20 DEG C, CH is dripped2Cl2(31mL) acyl chlorides dissolved, is slowly increased to room temperature reaction overnight after dropwising.TLC detects reaction, removes solvent under reduced pressure, obtains II-3 compound 21.2g through column chromatography for separation, yield 77.42%, mp180.0-181.9 DEG C.1HNMR (400MHz, CDCl3)δ1.98(-CH3, d, J=7.3Hz, 3H), 5.27 (-CH, q, J=7.5Hz, 1H), 7.42 (-Ph, dd, J1=4.2Hz, J2=8.3Hz, 1H), 7.51 (-Ph, s, 1H), 7.53 (-Py, d, J=9.0,1H), 7.65-7.85 (-Ph, m, 2H), 7.90 (-Ph, dt, J1=3.6, J2=7.1Hz, 2H), 8.15 (-Py, d, J=8.3Hz, 1H), 8.69 (-Ph, d, J=4.2Hz, 1H), 8.73 (-Py, dd, J1=4.7, J2=8.9Hz, 1H), 10.33 (-CONH, s, 1H).MS (ESI): m/z346.0 [M+H]+。
4, the preparation of (S)-2-amino-3-(4-(trifluoromethyl) phenyl) methyl propionate (IIa)
(1) preparation of (S)-2-(phthalimide-based)-N-(8-quinolyl)-3-(4-(trifluoromethyl) phenyl) propionic acid amide. (II-4a)
By Compound II per-3 (5.2g, 15mol) it is dissolved in the tert-butyl alcohol (105mL), add palladium (331mg, 1.5mmol), silver tetrafluoroborate (3.65g, 18.75mmol) and 4-iodine benzotrifluoride (6.12g, 22.5mmol), 85 DEG C of condensing reflux 24h, TLC detects reaction, after being warmed up to room temperature, uses CH2Cl2(100mL) dilution, adds triethylamine (10mL) and stirs 3h, and reactant liquor crosses kieselguhr, removes solvent under reduced pressure, obtains solid product 5.3g through column chromatography for separation, yield 72.1%, mp124.0-125.5 DEG C.1HNMR (400MHz, CDCl3)δ3.77-3.95(-CH2, m, 2H), 5.47 (-CH, dd, J1=6.9Hz, J2=9.7Hz, 1H), 7.39 (-Ph, dd, J1=4.3Hz, J2=8.3Hz, 1H), 7.42 (-Ph, d, J=8.1Hz, 2H), 7.49 (-Ph, d, J=8.2Hz, 2H), 7.51 (-Ph, s, 1H), 7.53 (-Py, t, J=5.5Hz, 1H), 7.68-7.78 (-Ph, m, 2H), 7.78-7.91 (-Ph, m, 2H), 8.12 (-Py, dt, J1=7.1Hz, J2=14.1Hz, 1H), 8.58 (-Ph, dd, J1=1.5Hz, J2=4.2Hz, 1H), 8.67-8.79 (-Py, m, 1H), 10.28 (-CONH, s, 1H).MS (ESI): m/z487.1 [M-H]-。
Other similar compounds all can adopt above-mentioned steps to prepare.
II-4b: iodo-for II-3 and 1-3,5-double; two (trifluoromethyl) benzene are adopted the method synthesis of embodiment (1)；II-4c: iodo-for II-3 and 6-Isosorbide-5-Nitrae-benzo dioxy alkane is adopted the method synthesis of embodiment (1)；II-4d: by II-3 and 2,4-dimethoxy iodobenzene adopts the method synthesis of embodiment (1).
The particular compound of synthesis and character such as following table thereof.
(2) preparation of (S)-2-(phthalimide-based)-3-(4-(trifluoromethyl) phenyl) methyl propionate (II-5a)
By Compound II per-5a (2g, 4.1mmol) it is dissolved in MeOH (94mL) in heavy wall pressure bottle, it is slowly added dropwise boron trifluoride ether solution (5.2mL, 40.9mmol), reacting at 100 DEG C overnight, TLC detects reaction, add triethylamine (8.6mL, 61.3mmol) stirring a period of time, remove solvent under reduced pressure, use CH2Cl2(30mL) dissolving, respectively with pickling (10% hydrochloric acid), alkali cleaning (5% sodium bicarbonate) and saturated common salt are washed, desiccant dryness (anhydrous sodium sulfate and anhydrous magnesium sulfate).Filter desiccant, evaporated under reduced pressure solvent, obtain oil product 1.3g, yield 83.2% through column chromatography for separation.1HNMR (400MHz, CDCl3)δ3.55-3.71(-CH2, m, 2H), 3.78 (-CH3, s, 3H), 5.18 (-CH, dd, J1=5.8Hz, J2=10.7Hz, 1H), 7.30 (-Ph, d, J=8.0Hz, 2H), 7.46 (-Ph, d, J=8.0Hz, 2H), 7.67-7.75 (-Ph, m, 2H), 7.79 (-Ph, dt, J1=3.6Hz, J2=7.1Hz, 2H).MS (ESI): m/z378.3 [M+H]+。
Other similar compounds all can adopt above-mentioned steps to prepare.
II-5b: II-4b adopts the method for embodiment (2) synthesize；II-5c: II-4c adopts the method for embodiment (2) synthesize；II-5d: II-4d adopts the method for embodiment (2) synthesize.
The particular compound of synthesis and character such as following table thereof.
(3) preparation of (S)-2-amino-3-(4-(trifluoromethyl) phenyl) methyl propionate (IIa)
By Compound II per-5a (745mg, 1.9mmol) it is dissolved in MeOH (19mL), add ethylenediamine (297mg, 4.9mmol), condensing reflux at 70 DEG C, TLC detects reaction, 5h reaction terminates, and filters, filtrate decompression solvent evaporated, oily target compound 311mg, yield 62.4% is obtained through column chromatography for separation.1HNMR (400MHz, DMSO) δ 2.84 (-CH2, dd, J1=7.7Hz, J2=13.3Hz, 1H), 2.95 (-CH2, dt, J1=9.5Hz, J2=19.0Hz, 1H), 3.59 (-CH3, s, 3H), 3.61 (-CH, d, J=6.9Hz, 1H), 7.40 (-Ph, t, J=11.9Hz, 2H), 7.59 (-Ph, t, J=21.6Hz, 2H).MS (ESI): m/z248.1 [M+H]+。
Other similar compounds all can adopt above-mentioned steps to prepare.
IIb: II-5b adopts the method for embodiment (3) synthesize；IIc: I-5c adopts the method for embodiment (3) synthesize；IId: II-5d adopts the method for embodiment (3) synthesize.
The particular compound of synthesis and character such as following table thereof.
Two, the preparation of compound in formula (III):
1, the preparation of glycine methyl ester hydrochloride (IIIa)
Being dissolved in MeOH (30mL) by Compound II per Ia (3g, 40mmol), cryosel bath is cooled to-10 DEG C, is slowly added dropwise SOCl under stirring2(29mL, 400mmol), reacts 10min after completion of dropwise addition, remove cryosel bath, react overnight under room temperature, and TLC detects reaction, concentrating under reduced pressure, adds 20mLCH2Cl2, concentrating under reduced pressure twice repeatedly, it is spin-dried for solvent, dry, obtain product 5g, yield 99.5%, product is not purified, is directly used in the next step.
The hydrochlorate of other amino acid methyl ester used in the present invention all can adopt above-mentioned steps to prepare.Compound II per Ib: adopt the synthesis of D-Cyclohexylglycine by the method for synthesis Compound II per Ia；Compound II per Ic: adopt the synthesis of L-Cyclohexylglycine by the method for synthesis Compound II per Ia；Compound II per Id: adopt phenylalanine synthesis by the method for synthesis Compound II per Ia.
The particular compound of synthesis and character such as following table thereof.
2, the preparation of L-O-methyl serine methyl ester hydrochloride (IIIe)
(1) preparation of BOC-L-O-methyl serine methyl ester (IIIe-1)
Being dissolved in acetone (110mL) by BOC-L-serine methylester (5g, 22.8mmol), add iodomethane (32mL, 524mmol) and silver oxide (8.2g, 35.4mmol), at 59 DEG C, lucifuge condensing reflux is overnight.TLC detects reaction, filters, removes solvent under reduced pressure, obtain oily target compound 1.8g, yield 34.5% through column chromatography for separation.1HNMR (400MHz, CDCl3)δ1.43(-CH3, s, 9H), 3.32 (-CH3, s, 3H), 3.57 (-CH2, dd, J1=3.4Hz, J2=9.4Hz, 1H), 3.74 (-CH3, d, J=6.3Hz, 3H), 3.78 (-CH2, dd, J1=3.1Hz, J2=9.4Hz, 1H), 4.35-4.44 (-CH, m, 1H), 5.28-5.44 (-CONH, m, 1H).MS (ESI): m/z234.2 [M+H]+。
(2) preparation of L-O-methyl serine methyl ester hydrochloride (IIIe)
By Compound II per Ie-1 (496mg, 2.1mmol) it is dissolved in ethyl acetate (2.5mL), ethyl acetate solution (the 5.2mL of HCl is dripped under ice bath, 21.2mmol), reacting under room temperature, TLC detects reaction, 2h reaction terminates, filtering, namely filter cake vacuum drying obtains pure products 351mg, yield 97.5%.1HNMR (400MHz, CDCl3)δ3.41(-CH3, s, 3H), 3.83 (-CH3, s, 3H), 3.95 (-CH2, dd, J1=3.6Hz, J2=10.4Hz, 1H), 4.03 (-CH2, dd, J1=2.6Hz, J2=10.3Hz, 1H), 4.45 (-CH, s, 1H), 8.70 (-NH3 +, s, 3H).
3, the preparation of S-methyl-Lcysteine methyl ester hydrochloride (IIIf)
(1) preparation of S-methyl-Lcysteine (IIIf-1)
By L-cysteine hydrochloride monohydrate (3.1g, 17.5mmol) be dissolved in MeOH (45mL), methanol solution (the 11.2g of the Feldalat NM of 30% is dripped under ice bath, 62mmol), after reaction 1h, dropping iodomethane (0.9mL, 13.mmol), is warming up to room temperature reaction, TLC detects reaction, 2h reaction terminates, and adjusts pH value to 5 with 10NHCl, adds 40mL ether stirring 10min, filter, filter cake 60mL washed with diethylether, vacuum drying, obtain thick product 4.715g.
(2) preparation of S-methyl-Lcysteine methyl ester hydrochloride (IIIf)
Being dissolved in MeOH (25mL) by S-methyl-Lcysteine (4.715g, 34.9mmol), cryosel bath is cooled to-10 DEG C, is slowly added dropwise SOCl under stirring2(25mL, 348.8mmol), reacts 10min after completion of dropwise addition, remove cryosel bath, react overnight under room temperature, and TLC detects reaction, filters, filter cake CH2Cl2Washing, namely vacuum drying obtains pure S-methyl-Lcysteine methyl ester hydrochloride 3.1g, yield 95.4%.1HNMR (400MHz, D2O) δ 4.44 (-CH, dd, J=7.7,4.6Hz, 1H), 3.90 (-CH3, s, 3H), 3.23 (-CH2, dd, J=15.1,4.6Hz, 1H), 3.14-3.07 (-CH2, m, 1H), 2.18 (-CH3, s, 3H).
Three, the preparation of compound in formula (I):
1, the preparation of (S)-N-(2,5-dichloro-benzoyl base)-3-(4-trifluoromethyl) methyl lactamine (I-1a)
2,5-dichlorobenzoic acids (90mg, 0.47mmol) and HOBt (92mg, 0.7mmol) are dissolved in CH2Cl2(8mL) in, 10min is reacted at-10 DEG C, add EDC HCl (135mg, 0.7mmol) react 30min, add Compound II per a (116mg, 0.47mmol), after reaction 10min, add DIPEA (151mg, 1.17mmol), room temperature reaction is risen to overnight after reaction 20min.TLC detects reaction, respectively with the hydrochloric acid solution (10mL) of 10%, the NaHCO of 5%3Solution (10mL) and saturated aqueous common salt (2 × 10mL) washing, CH2Cl2Layer anhydrous Na2SO4Dry, filter, remove solvent under reduced pressure, obtain oily compound 166mg, yield 84.3%.Product is not purified, is directly used in the next step.
The product yield obtained in view of EDC HCl condensation method is high, so the unprotected amino acid methyl ester of other amino used in the present invention can adopt the EDC HCl condensation method described in embodiment 1 to prepare, and all non-purification of all methyl ester, it is directly used in the next step.
Compound I-1b: utilize 2.5-dichlorobenzoic acid and IIb synthesis by EDC HCl condensation method；Compound I-1c: utilize 2.5-dichlorobenzoic acid and IIc synthesis by EDC HCl condensation method；Compound I-1d: utilize 2.5-dichlorobenzoic acid and IId synthesis by EDC HCl condensation method.
(1), the preparation of (S)-N-(2,5-dichloro-benzoyl base) glycine methyl ester (I-1e)
2,5-dichlorobenzoic acids (7.6g, 40mmol) and HOBt (8.1g, 40mmol) are dissolved in CH2Cl2(200mL) in, 10min is reacted at-10 DEG C, add EDC HCl (11.5g, 60mmol) react 30min, add Compound II per Ia (5g, 40mmol), after reaction 10min, add DIPEA (18.1g, 140mmol), room temperature reaction is risen to overnight after reaction 20min.TLC detects reaction, respectively with the hydrochloric acid solution (200mL) of 10%, the NaHCO of 5%3Solution (200mL) and saturated aqueous common salt (2 × 200mL) washing, CH2Cl2Layer anhydrous Na2SO4Dry, filter, remove solvent under reduced pressure, obtain oily compound 9.32g, yield 88.9%.Product is not purified, is directly used in the next step.
Compound I-1f: utilize 2.5-dichlorobenzoic acid and IIIb synthesis by EDC HCl condensation method；Compound I-1g: utilize 2.5-dichlorobenzoic acid and IIIc synthesis by EDC HCl condensation method；Compound I-1h: utilize 2.5-dichlorobenzoic acid and IIIe synthesis by EDC HCl condensation method；Compound I-1i: utilize 2.5-dichlorobenzoic acid and IIIf synthesis by EDC HCl condensation method；Compound I-1j: utilize 2-pyrazine carboxylic acid and IIa synthesis by EDC HCl condensation method；Compound I-1k: utilize 2-pyrazine carboxylic acid and IIc synthesis by EDC HCl condensation method；Compound I-1l: utilize 5,6,7,8-tetrahydrochysene-1-naphthoic acids and IIc synthesis by EDC HCl condensation method；Compound I-1m: utilize 5-methylisoxazole-3-formic acid and IIIa synthesis by EDC HCl condensation method.Compound I-1n: utilize 5-methyl-2-pyrazine carboxylic acid and IIId synthesis by EDC HCl condensation method.
The amino acid methyl ester of other amido protecting used in the present invention can adopt the EDC HCl condensation method described in embodiment (1) to prepare, and all non-purification of all methyl ester is directly used in the next step.
(2), the preparation of (S)-N-(Methoxyacetyl) phenyalanine methyl ester (I-1o)
2-Methoxyacetic acid (280mg, 3.13mmol) is dissolved in CH2Cl2(6mL), dropping SOCl at-10 DEG C2(0.25mL, 3.45mmol).Room temperature reaction 2h is risen to after dropwising.Methoxyacetyl chloride solution directly throws next step.IIId (0.67g, 3.13mmol) is dissolved in 3mLCH2Cl2In, adding triethylamine (1.58g, 15.65mmol), drip methoxyacetyl chloride solution, reaction is overnight.TLC detects reaction, washes with water, Na2SO4Dry, obtain oily target compound 0.69g, yield 87.3% through column chromatography for separation.
Compound I-1p: utilize 3-methoxypropionic acid and IIId synthesis by acyl chlorides condensation method；Compound I-1q: utilize butanoic acid and IIId synthesis by acyl chlorides condensation method；Compound I-1r: utilize ethylene-acetic acid and IIId synthesis by acyl chlorides condensation method；Compound I-1s: utilize cyclopenta formic acid and IIId synthesis by acyl chlorides condensation method.
The amino acid methyl ester of other amido protecting used in the present invention and alkyl acid can adopt the condensation method described in embodiment (2) to prepare, and all non-purification of all methyl ester is directly used in the next step.
The particular compound of synthesis and character such as following table thereof.
2, the preparation of (S)-N-(2,5-dichloro-benzoyl base)-3-(4-trifluoromethyl) alanine (I-2a)
Compound I-1a (129mg, 0.31mmol) 2.5mLMeOH is dissolved, adds LiOH H2O (39mg, 0.92mmol) and H2O (0.8mL), TLC detect, and react complete after 2h.Being spin-dried for organic facies, by ether (2 × 1mL) aqueous phase extracted, aqueous phase dropping hydrochloric acid is 2～3 to pH value, produces a large amount of white solid, extraction into ethyl acetate, remove solvent under reduced pressure, obtain white products 106mg, yield 86.0%, mp185.1-186.9 DEG C.1HNMR (400MHz, DMSO) δ 3.02 (-CH2, dd, J1=10.6Hz, J2=13.8Hz, 1H), 3.30 (-CH2, dd, J1=4.6Hz, J2=13.9Hz, 1H), 4.68 (-CH, ddd, J1=4.7Hz, J2=8.4Hz, J3=10.4Hz, 1H), 7.15 (-Ph, d, J=1.8Hz, 1H), 7.49 (-Ph, t, J=4.9Hz, 2H), 7.52 (-Ph, d, J=6.0Hz, 2H), 7.66 (-Ph, d, J=8.1Hz, 2H), 8.90 (-CONH, d, J=8.2Hz, 1H), 13.12 (-COOH, s, 1H).MS (ESI): m/z403.9 [M-H]-。
The aminoacid of other amido protecting used in the present invention can adopt the method described in embodiment 2 to prepare.
Compound I-2b: I-1b adopts the method for embodiment 2 synthesize；Compound I-2c: I-1c adopts the method for embodiment 2 synthesize；Compound I-2d: I-1d adopts the method for embodiment 2 synthesize；Compound I-2e: I-1e adopts the method for embodiment 2 synthesize；Compound I-2f: I-1f adopts the method for embodiment 2 synthesize；Compound I-2g: I-1g adopts the method for embodiment 2 synthesize；Compound I-2h: I-1h adopts the method for embodiment 2 synthesize；Compound I-2i: I-1i adopts the method for embodiment 2 synthesize；Compound I-2j: I-1j adopts the method for embodiment 2 synthesize；Compound I-2k: I-1k adopts the method for embodiment 2 synthesize；Compound I-2l: I-1l adopts the method for embodiment 2 synthesize；Compound I-2m: I-1m adopts the method for embodiment 2 synthesize；Compound I-2n: I-1n adopts the method for embodiment 2 synthesize；Compound I-2o: I-1o adopts the method for embodiment 2 synthesize；Compound I-2p: I-1p adopts the method for embodiment 2 synthesize；Compound I-2q: I-1q adopts the method for embodiment 2 synthesize；Compound I-2r: I-1r adopts the method for embodiment 2 synthesize；Compound I-2s: I-1s adopts the method for embodiment 2 synthesize.
The particular compound of synthesis and character such as following table thereof.
3, (S)-N-(2,5-dichloro-benzoyl base)-3-(4-trifluoromethyl) propionic acid amide .-D-Leu boric acid-(+) preparation of-australene alkane diol ester (I-3a)
Compound I-2a (340mg, 0.84mmol) and HOBt (218g, 1.67mmol) is dissolved in CH2Cl2(18mL) in, at-10 DEG C, react 10min, add EDC HCl (321mg, 1.67mmol) and react 30min, add (aR, 3aS, 4S, 6S, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetate (317mg, 0.84mmol), add DIPEA (433mg, 3.35mmol) after reaction 10min, after reaction 20min, rise to room temperature reaction overnight.TLC detects reaction, respectively with the hydrochloric acid solution (20mL) of 10%, the NaHCO of 5%3Solution (20mL) and saturated aqueous common salt (2 × 20mL) washing, CH2Cl2Layer anhydrous Na2SO4Dry, filter, remove solvent under reduced pressure, obtain oily target compound 480mg, yield 87.6% through column chromatography for separation.1HNMR (400MHz, CDCl3)δ0.82(-CH3, s, 3H), 0.85 (-CH3, s, 6H), 1.16 (-CH2, dd, J1=7.8HzJ2=10.8Hz, 1H), 1.28 (-CH3, s, 3H), 1.32 (-CH2, d, J=14.3Hz, 1H), 1.39 (-CH3, s, 3H), 1.41-1.52 (-CH, m, 1H), 1.63 (-CH, s, 1H), 1.81 (-CH2, dd, J1=2.8Hz, J2=14.5Hz, 1H), 1.90 (-CH2, d, J=2.4Hz, 1H), 1.98-2.05 (-CH, m, 1H), 2.12-2.23 (-CH2, m, 1H), 2.25-2.38 (-CH2, m, 1H), 3.19 (-CH, dd, J1=8.5Hz, J2=13.7Hz, 1H), 3.23-3.31 (-CH2, m, 2H), 4.21-4.34 (-CH, m, 1H), 4.75-4.94 (-CH, m, 1H), 5.90 (-CONH, dd, J1=5.6Hz, J2=22.2Hz, 1H), 6.94 (-CONH, d, J=7.7Hz, 1H), 7.29-7.36 (-Ph, m, 2H), 7.41 (-Ph, dd, J1=4.2Hz, J2=7.8Hz, 2H), 7.51 (-Ph, s, 1H), 7.55 (Ph, dd, J1=3.7Hz, J2=8.0Hz, 2H).MS (ESI): m/z653.2 [M+H]+。
The aminoacid of other amido protecting used in the present invention can adopt the method described in embodiment 3 to prepare.
Compound I-3b: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2b synthesis；Compound I-3c: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2c synthesis；Compound I-3d: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2d synthesis；Compound I-3e: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2e synthesis；Compound I-3f: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2f synthesis；Compound I-3g: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2g synthesis；Compound I-3h: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2h synthesis；Compound I-3i: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2i synthesis；Compound I-3j: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2j synthesis；Compound I-3k: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2k synthesis；Compound I-3l: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2l synthesis；Compound I-3m: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2m synthesis；Compound I-3n: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2n synthesis；Compound I-3o: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2o synthesis；Compound I-3p: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2p synthesis；Compound I-3q: utilize (aR, 3aS, 4S, 6S by EDC HCl condensation method, 7aR)-hexahydro-3a, 8,8-trimethyl-alpha-(2-methyl-propyl)-4,6-methano-1,3,2-benzo dioxy borine-2-methylamine 2,2,2-trifluoroacetates and I-2q synthesis.
The particular compound of synthesis and character such as following table thereof.
4, the preparation of (S)-N-(2,5-dichloro-benzoyl base)-3-(4-trifluoromethyl) propionic acid amide .-D-Leu boric acid (IV-1)
By compound I-3a (317mg, 0.49mmol) it is dissolved in the MeOH of 3mL, is sequentially added into isobutaneboronic acid (247mg, 2.43mmol), normal hexane (3mL) and 1NHCl (1.2mL, 1.2mmol), reaction stirring is overnight.TLC detects reaction, and normal hexane extracts 2 times with MeOH (2 × 3mL) mutually, and normal hexane (3mL) washs methanol phase 1 time, removes methanol, CH under reduced pressure2Cl2(2 × 2mL) aqueous phase extracted 2 times, washs organic facies to aqueous phase in neutrality with saturated aqueous common salt (3 × 5mL).Remove solvent under reduced pressure, obtain pure products 193mg, yield 76.5% through column chromatography for separation.1HNMR (400MHz, CDCl3)δ1.18(-CH3, s, 3H), 1.25 (-CH3, s, 3H), 2.13-2.41 (-CH2, m, 2H), 2.45-2.61 (-CH, m, 1H), 3.20-3.58 (-CH2, m, 2H), 3.58-3.71 (-CH, m, 1H), 5.21-5.62 (-CH, m, 1H), 7.62-7.75 (-Ph, m, 4H), 7.84 (-Ph, t, J=13.5Hz, 3H).13CNMR(CDCl3, 100MHz) and δ 22.67,27.21,31.90,35.60,51.28,54.80,125.37,125.55,128.92,129.05,129.47,129.76,129.85,131.34,131.60,133.12,133.17,139.92,165.18,170.98.MS (ESI): m/z517.1 [M-H]-, calcd:518.1.HRMS (ESI): calcdforC22H24BCl2F3N2NaO4[M+Na]+541.1054, found541.1118.
The synthesis of other the boric acid compound of the present invention can be adopted with the aforedescribed process.
Concrete compound is as shown in the table.
Above-described boric acid compound can generate boric acid ester compound with the reaction such as citric acid and use as prodrug, preparation method in the following example described in, but be not limited to this example:
5, the preparation of (S)-N-(2,5-dichloro-benzoyl base) acetamide-D-Leu boric acid diethanolamine ester (V)
Diethanolamine (160mg, 1.52mmol) is dissolved in 8mL ethyl acetate, is warming up to 74 DEG C, adding the MLN2238 (500mg, 1.38mmol) being dissolved in 1.5mL ethyl acetate, slow cooling is to 60 DEG C, reaction 3h, then slow cooling is to 25 DEG C overnight.TLC detects reaction, filters, and filter cake vacuum drying obtains pure products 557mg, yield 85.4%.Yield 93.6%.1HNMR (400MHz, DMSO) δ 0.79 (-CH3, d, J=6.4Hz, 3H), 0.82 (-CH3, d, J=6.7Hz, 3H), 1.12-1.39 (-CH2, m, 2H), 1.60 (-CH, s, 1H), 2.65-3.06 (-CH2, m, 4H), 3.14 (-CH, dd, J1=6.6Hz, J2=10.8Hz, 1H), 3.30-3.73 (-CH2, m, 4H), 3.74-3.89 (-CH2, m, 2H), 6.58 (-NH, s, 1H), 6.98 (-CONH, d, J=8.1Hz, 1H), 7.54 (-Ph, d, J=10.9Hz, 3H), 8.83 (-CONH, s, 1H).13CNMR (DMSO, 100MHz) δ 21.67,23.97,24.53,50.49,50.92,62.44,128.67,128.85,130.75,131.50,131.61,137.83,165.25,167.73.HRMS (ESI): calcdforC18H26BCl2N3NaO4[M+Na]+452.1289, found452.1299.
Other the prodrug compound of the present invention can be adopted and synthesize with the aforedescribed process.
Part II protease inhibition body determination of activity
Proteasome inhibition activity
This patent utilizes fluorescent peptide substrates Suc-Leu-Leu-Val-Tyr-AMC (write a Chinese character in simplified form Suc-LLVY-AMC, Suc and represent that succinyl group, AMC represent 7-amide-4-methylcoumarin) to measure the enzymatic activity of the Chymotrypsin sample of proteasome.
Proteasome used by this patent is human red blood cell 20S proteasome, and enzyme, fluorogenic substrate and assay buffer are all purchased from Enzo company.Experimental system is 16 μ L, wherein substrate 8 μ L, proteasome 4 μ L (0.8ng), and ultimate density is 50 μMs, and medicine (inhibitor) 4 μ L, ultimate density is 2 × 10-6M～4.88 × 10-10M, last concentration is 0M, and actual disposition concentration is 8 × 10-6M～1.95 × 10-9M, last concentration is 0M.Specific experiment process is as follows:
1, medicine ordinance:
Weighing medicine, it is 10 that addition DMSO is dissolved to concentration-2M.Draw 2 μ L with liquid-transfering gun to add to 98 μ LDMSO and obtain 2 × 10-4M, then again from 2 × 10-4M acute drug is drawn 8 μ L and adds 19g μ LH2O obtains 8 × 10-6M, utilizes same method to obtain 2 × 10-6M、5×10-7M、1.25×10-7M、3.12×10-8M、7.8×10-9M、1.95×10-9The medicine of M concentration, last concentration 0M is not dosing.
2, prepared by substrate:
25mg fluorescent peptide substrates is dissolved in 654 μ LDMSO, obtains 50mM storing solution, in-20 DEG C of preservations, dilute 500 times during use, every part of sample adds 8 μ L so that the final concentration of substrate in reaction system is 50 μMs.
3, prepared by reaction system:
With buffer solution, 20S proteasome (2ng/ μ L) is diluted to the solution that concentration is 8ng/ μ L, joining in 384 hole luciferase targets, every hole adds 4 μ L, then adds 4 μ L testing samples in every hole, using marketed drug Bortezomib is positive control drug, reacts 15min at 37 DEG C.After reaction terminates, every hole adds 8 μ L fluorogenic substrates, and 37 DEG C of lucifuges are reacted 1 hour, utilize 360nm/460nm fluorescence microplate reader (BMGLABTECHPOLARstarOPTIMAMicroplateReader) to detect fluorescent value.
4, data process
After calculating deduction background, the fluorescent value of products therefrom under the medicine effect of variable concentrations, uses GraphPadPrism software, calculates the IC that proteasome is suppressed by medicine50Concentration.
The result of part of compounds such as following table:
Compound number IC50(nM) Compound number IC50(nM) Compound number IC50(nM)
IV-1 8.315 IV-9 5.188 IV-17 6.94
IV-2 25.02 IV-10 42.61 IV-18 13.39
IV-3 2.595 IV-11 12.32 IV-19 7.19
IV-4 4.597 IV-12 15.02 V 7.139
IV-5 7.734 IV-13 222.6 Velcade 7.035
IV-6 82.03 IV-14 26.24 MLN2238 7.734
IV-7 3.229 IV-15 6.31 MLN9708 13.06
IV-8 9.956 IV-16 8.47
Wherein the chemical structural formula of Velcade and MLN9708 is:
Cell strain inhibitory activity
The detection liquid that this patent utilizes is single Solution Cell Proliferation detection box, from Promega company；Cell used is U266, RPMI8226, ARH77.Experimental system is 110uL, wherein contains cell suspension 90 μ L, detects liquid 10 μ L, and medicine (inhibitor) 10 μ L, they are final concentration of 4.54 × 10 years old-8M～1.77 × 10-9M, last concentration is 0M, and actual disposition concentration is 5 × 10-7M～1.95 × 10-8M, last concentration is 0M.Specific experiment process is as follows:
1, medicine ordinance:
Precise medicine, adds DMSO and is dissolved to 10-2M.Draw 1 μ L with pipettor to add to 199 μ LDMSO and obtain 5 × 10-5M, then from 5 × 10-5M acute drug is drawn 3.3 μ L add the RPMI1640 culture medium of 326.7 μ L serum-frees and obtain 5 × 10-7M, 1.5 times of gradient dilutions, obtain 3.3 × 10-7M、2.2×10-7M、1.48×10-7M、9.87×10-8M、6.58×10- 8M、4.38×10-8M、2.92×10-8M、1.95×10-8The medicine of M concentration, last concentration 0M is not dosing.
2, cell suspension configuration:
After cell counts respectively, dilution configuration U266 is 1 × 104Individual/hole, RPMI8226 and ARH77 is 1 × 104Individual/hole.
3, prepared by reaction system:
In 96 hole luciferase targets, every hole adds cell suspension 90 μ L, hatches 24h；Then adding 10 μ L testing samples in every hole, using marketed drug Bortezomib is positive control drug, hatches 24h；After completion of the reaction, every hole adds 10 μ L and detects liquid, hatches 2-3h, 490nm fluorescence microplate reader (BMGLABTECHPOLARstarOPTIMAMicroplateReader) detects absorbance.
4, data process
After calculating deduction background, the absorbance of products therefrom under variable concentrations medicine effect, uses GraphPadPrism software, calculates medicine to Cytotoxic IC50Concentration.
The result of part of compounds such as following table:
Numbering RPMI8226 ARH-77 U266B1 Numbering RPMI8226 ARH-77 U266B1
IV-1 233.7 98.15 100.4 IV-12 41.16 35.52 58.38
IV-2 186.6 154.60 217.3 IV-15 4.567 5.726 6.041
IV-3 17.84 10.06 9.42 IV-16 7.326 9.039 11.58
IV-4 37.78 14.58 18.66 IV-17 5.613 7.875 8.509
IV-5 55.32 65.50 52.15 IV-18 8.170 12.37 6.426
IV-7 97.03 69.46 65.8 IV-19 3.985 6.869 2.764
IV-8 8.99 9.10 6.75 V 43.45 28.06 34.93
IV-9 8.97 8.85 6.45 Velcade 11.2 9.57 11.63
IV-10 150.4 58.03 79.89 MLN2238 55.32 65.50 52.15
IV-11 43.44 29.26 30.26 MLN9708 49.74 43.25 67.1
The therapeutic dose of compound designed in the present invention can determine according to the mode of administration, the purposes for the treatment of, the health status of patient and the prescription of doctor.In composition of medicine, the concentration of compound designed by the present invention and proportion will change with many factors, including route of administration, dosage and chemical characteristic (as dredged.Such as, the compound designed by the present invention can be provided in in the aqueous physiological buffer containing about 0.1 to 10%w/v compound of parenterai administration.The dosage range of some routines is about 1 μ g/kg to 1g/kg every day.In a particular embodiment, dosage range from every day about 10 μ g/kg body weight to 100mg/kg body weight.Dosage can change according to the type of route of administration, the health status of patient, disease or imbalance and progress extent, the relative bioavailability of compound and the formula of excipient.Effective dosage can be extrapolated from external or animal model test system dose-effect curve.

Claims (10)

1. peptide boric acid and ester type compound thereof or its pharmaceutical salts, its structure shown in formula I,
Wherein:
R1Selected from C1～10Alkyl, C1～10Alkoxyl, C1～10Alcoxyl C1～10Alkyl, phenyl, naphthyl, tetralyl or heterocyclic radical, or optionally by C1～4Alkyl, C1～4Alkoxyl, C1～4Cycloalkyl, halogen or halo C1～4Alkyl replaces；
R2Selected from C1～10Alkyl, C3～6Cycloalkyl or Heterocyclylalkyl, phenyl, naphthyl or indyl, or optionally by C1～4Alkyl, C1～4Alkoxyl, cyano group, nitro, hydroxyl, sulfydryl, amino or halogen substiuted；
Z1Or Z2Independently selected from hydroxyl, C1～10Alkyl, C1～10Alkoxyl or aryloxy group, or B, Z1And Z2Collectively form the heterocyclic group containing N, S or O or B and Z1And Z2Collectively form the group containing O heterocycle, and what be connected with boron atom is oxygen atom.
2. peptide boric acid according to claim 1 and ester type compound thereof or its pharmaceutical salts, it is characterised in that described R1Selected from C1～10Alkyl, C1～10Alkoxyl, C1～10Alkoxyl-methyl, C1～10Alkoxyl oxygen alkyl ethyl, phenyl, pyrazinyl, pyridine radicals, naphthyl, tetralyl, or optionally by C1～4Alkyl, C1～4Alkoxyl, halogen or halo C1～4Alkyl replaces.
3. peptide boric acid according to claim 1 and ester type compound thereof or its pharmaceutical salts, it is characterised in that described in
R1It is selected from:
Wherein R3And R4Independently selected from hydrogen, methyl, methoxyl group, ethyl, ethyoxyl, chlorine, bromine, fluorine or trifluoromethyl.
4. peptide boric acid according to claim 1 and ester type compound thereof or its pharmaceutical salts, it is characterised in that described R2Selected from phenyl, methoxyl group, first sulfydryl, cyclohexyl, or optionally by C1～4Alkyl, C1～4Alkoxyl, nitro or halogen substiuted.
5. peptide boric acid according to claim 1 and ester type compound thereof or its pharmaceutical salts, it is characterised in that described Z1Or Z2Independently selected from hydroxyl, C1～10Alkyl, C1～10Alkoxyl or aryloxy group, or B, Z1And Z2Collectively form boric acid-australene alkane diol ester or B and Z1And Z2Collectively form borate, and what be connected with boron atom is oxygen atom.
6. peptide boric acid according to claim 1 and ester type compound thereof or its pharmaceutical salts, it is characterised in that described Z1Or Z2It is independently selected from hydroxyl or B, Z1And Z2Collectively form boric acid-australene alkane diol ester or B, Z1And Z2Collectively form diethanolamine ester and other prodrugs.
7. compound or pharmaceutically acceptable salt thereof, is selected from:
8. pharmaceutical composition, it comprises the compound any one of pharmaceutical carrier and claim 1-7, optional simultaneously, respectively or sequentially with one or more combination with other therapeutic agents.
9. the purposes in preparing proteasome inhibitor of the compound any one of claim 1-7.
10. the purposes in preparation treatment disease medicament of the compound any one of claim 1-7, it is characterized in that described disease is selected from: solid tumor and blood tumor, wherein solid tumor is selected from nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate, hepatocarcinoma, skin carcinoma, cell carcinoma, gastrointestinal stromal tumors (GISTs) or nasopharyngeal carcinoma, leukemia.Blood tumor is selected from multiple myeloma, lymphoma mantle cell and histiocytic lymphatic cancer.
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